The role of excitatory amino acids (EAA), such as glutamic acid and aspattic acid, as the predominant mediators of excitatory synaptic transmission in the central nervous system has been well established. Watkins & Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). These amino acids function in synaptic transmission primarily through excitatory amino acid receptors. The excitatory amino acids also participate in a variety of other physiological processes such as motor control, respiration, cardiovascular regulation, sensory perception, and cognition.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane or the neurons are termed "ionotropic."This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), .alpha.-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor. This second type, when activated by the agonists quisqualate, ibotenate, or trans-1-aminocyclopentane-1,3-dicarboxylic acid, leads to enhanced phosphoinositide hydrolysis in the postsynaptic cell. Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development. These receptors also affect changes in the efficiency of synaptic transmission throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. Excitatory amino acid excitotoxicity has been implicated in the pathophysiology of a number of neurological disorders. This excitotoxicity has been implicated in the pathophysiology of acute and chronic neurodegenerative conditions including cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, perinatal hypoxia, cardiac arrest, hypoglyemic neuronal damage, ocular damage and retinopathy, and idiopathic and drug-induced Parkinson's Disease. Other neurological conditions, that are caused by glutamate dysfunction, may require neuromodulation. These other neurological conditions include muscular spasms, migraine headaches, urinary incontinence, psychosis, opiate tolerance and withdrawal, anxiety, emesis, brain edema, chronic pain, convulsions, and tardive dyskinesia. The use of a neuroprotective agent, such as an EAA receptor antagonist, is believed to be useful in treating these disorders and/or reducing the amount of neurological degeneration associated with these disorders. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.
A recent report shows that a series of 6-substituted decahydroisoquinoline-3-carboxylic acids act as competitive NMDA receptor antagonists and are suitable for use as neuroprotective agents in a variety of acute and chronic neurodegenerative disorders. Ornstein et al., J. Med. Chem., 35, 3547-3560 (1992). One compound from this series, (.+-.)-(3SR,4aRS, 6SR, 8aRS)-6-(phosphonomethyl)-decahydroisoquinoline-3-carboxylic acid, is a very potent and selective neuroprotective agent against excessive NMDA receptor activation in vivo when administered systemically in rats and in mice. Schoepp, ornstein, Salhoff, and Leander, J. Neural Transm., 85, 131-143 (1991). This compound effectively blocks NMDA-induced convulsions in neonatal rats. This compound also provides neuroprotection against NMDA receptor-induced lethality in mature mice and rats. Surprisingly, the 3S isomer of this compound is active as an NMDA receptor antagonist, while the 3R isomer is inactive. Ornstein & Klimkowski, Excitatory Amino Acid Receptors: Design of Agonists and Antagonists, 183-200 (1992). Therefore, this agent, as well as other compounds in the series, may prove therapeutically useful in treating acute pathological conditions that involve glutamate excitotoxicity.